Six generations of epidermolytic palmoplantar keratoderma, associated with a KRT9 R163W mutation.

Epidermolytic palmoplantar keratoderma (EPPK) is a rare autosomal dominant skin disorder characterized by diffuse hyperkeratosis on the palms and soles. Whole-exome sequencing (WES) has become a powerful tool for the detection of rare causal variants of Mendelian disorders. However, no causal gene for EPPK in the Uygur population has been identified until now, and no treatment exists than can address the underlying pathology.WES analysis was undertaken on two individuals from a large Uygur EPPK pedigree whose disease locus mapped to 17q21.2 (chr:38994621-39893408) following previous linkage analysis. KRT9 (NM_000226.3:c.487C>T, p.Arg163Trp), and KRT15 (XM_005257346.1:c.212G>T, XP_005257403.1:p.Gly71Val) located in this region, have been identified as two candidate causative genes for EPPK in the Uygur family. Sanger sequencing was conducted on this region in other affected individuals (n = 38) from this family, non-affected individuals (n = 56) from this family and 100 unrelated controls. The missense mutation KRT9 c.487C>T, identified in this large Uygur population, is a potential causative mutation. To date, EPPK has no effective therapy, and siRNA is a potential avenue for EPPK therapy. To investigate this, full-length wild-type Keratin9 (KRT9; pKRT9-WT) and p.Arg163Trp (pKRT9-R163W) were then transfected into HaCaT cells. The small interfering RNAs targeting the KRT9 R163W mutant and wildtype KRT9 were transfected into HaCaT cells, and total RNA isolated at 72 h post-transfection. Quantitative polymerase chain reaction and western blotting were used to analyse the effects of knock-down on KRT9 mRNA and protein levels, respectively. siRNA was shown to specifically inhibit mutant KRT9 mRNA and protein expression (p < 0.01, with 95% confidence limits). Our study suggests that KRT9 is a causal gene for EPPK. This information is helpful for understanding the pathogenesis of EPPK in the Uygur population and raises the possibility of designing a novel siRNA treatment strategy for this population of EPPK patients.